Peptide drugs represent a market of approximately 1000 million US dollars and about 1% of the total sales of active pharmaceutical ingredients. There are currently more than forty synthetic peptides in the market and more than 500 new peptide molecules are being developed.
The chemistry of peptides is a very important area of research since these compounds have interesting biological and therapeutic properties. Likewise, non-proteinogenic amino acids are increasingly more important as intermediates of said peptides with biological and therapeutic activity.
It is known that the activity of a drug depends on the conformation it is able to adopt in its interaction with the receptor and in turn, in the case of peptide compounds such conformation depends on the amino acids present in the chain. Therefore, one way of modifying their activity as drugs is to introduce conformationally restricted analogs of the amino acids forming part of the sequence of the biologically active peptide (cf. e.g. T. Osaka et al., Current Opinion in Chemical Biology 2002, vol. 6, pp. 809-815; D. R. Hodgson et al., Chem. Soc. Rev 2004, vol. 33, pp. 422-430).
The use of non-natural amino acids increases the half life of the corresponding peptides that are more easily broken down by proteases. It has also been described that the substitution of phenyl with mesityl (2,4,6-trimethylphenyl) in several amino acids considerably increases rotational barriers without significantly changing the geometry of the most stable conformer (cf. E Medina et al., Helv. Chim. Acta 2000, vol. 83, pp. 972-988). With this substitution of phenylalanine with mesityl alanine, peptide analogs with great biological activity have been prepared, such as analogs of [D-har8]vasopressin (cf. M. Zertova et al., Collect. Czech. Chem. Comun. 1993, vol. 58, pp. 2751), analgesics and antihypertensive agents (cf. EP 0213481 A2), analogs of encephalin (cf. EP 0136720 A2), analogs of the LHRH hormone (cf. EP 0049628 A1) and peptides with fibroin sequences. The preparation of those analogs has been carried out by incorporation of the amino acid protected with the Boc protecting group in racemic form and the resulting peptides have subsequently been separated by HPLC with a chiral stationary phase (cf. J. Hlavaceck et al., Collect. Czech. Chem. Comun., 1991, vol. 56, p. 2991).
L-phenylalanine is a natural amino acid natural present in most natural peptides and proteins. Mesityl alanine is a non-natural amino acid useful for preparing several peptides and peptide analogs. Mesityl alanine has been prepared in racemic form and has been analytically but not preparatively separated. However, the use of mesityl alanine is rather uncommon so far, probably due to the difficulties found in preparing enantiomerically pure amino acids containing the mesityl group in the side chain.
E. Medina et al. have described a synthesis of mesityl amino acids based on Sharpless epoxidation and Sharpless aminohydroxylation (cf. Helv. Chim. Acta 2000, vol. 83, pp. 972-988). However, this synthesis has significant drawbacks which hinder its use on an industrial level. Among such drawbacks stands out that a very low conversion is obtained in the Sharpless epoxidation of mesityl propenol, and the crude products from the aminohydroxylation reaction need to be chromatographed to eliminate excessive residues. A synthesis of L-mesityl alanine hydrochloride by means of enantioselective asymmetric catalytic hydrogenation of an acetamidoacrylate precursor has been also described (cf. T. Li et al., Chem. Pharm. Bull. 2006, vol. 54, pp. 873-877).
The teachings of all these documents from the state of the art show that the research of new processes for preparing L- or D-mesityl amino acids is still an active field, particularly of L- or D-mesityl alanine, amino acids which are useful for preparing different peptides and peptide analogs with great biological activity but which have not been widely used until now due to the complexity of the known preparation processes for preparing enantiomerically pure amino acids containing this group.